Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.

TLR-9 agonists are immunostimulating agents that have antitumor effects in animal models. A phase I trial was conducted to define the safety profile of subcutaneous injections, combined with intrathecally administration of CpG-28, a TRL 9 agonist, in patients with neoplastic meningitis (NM). Cohorts of 3-6 patients with NM were treated for 5 weeks with escalating doses of CpG-28. The primary endpoint was tolerance. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Twenty-nine patients were treated with CpG-28. The primary cancers were malignant glioma, lung carcinoma, breast cancer, melanoma or melanocytoma, ependymoma, and colorectal cancer. The median age was 56 years and median Karnovsky Performance status (KPS) was 70%. The treatment was well tolerated. Adverse effects that were possibly or probably related to the studied drug were grade 2 lymphopenia, anemia and neutropenia, local erythema at injection sites, fever and seizure. There were five serious adverse events: two confusions, two infections of ventricular devices and one grade 4 thrombopenia and neutropenia. The median PFS was 7 weeks and median OS was 15 weeks. Interestingly, the median survival was slightly (but not significantly) higher in the eight patients who were concomitantly treated with bevacizumab (19 weeks vs 15 weeks; P = 0.11). CpG-28 was well tolerated at doses up to 0.3 mg/kg subcutaneously and 18 mg intrathecally. Additional trials are warranted.

Evolution of the Karnosky Performance Status throughout life in glioblastoma patients.

Functional independence in glioblastoma (GBM) patients is a key factor in measuring the quality of life. Progression free survival (PFS) and overall survival (OS) have been largely described. However, the evolution over time of the performance status during the patients' life remains understudied. We thus studied the time to loss of functional independence as assessed by a Karnosky Performance Status (KPS) below 70 % in GBM patients. We analysed all GBM patients treated in our institution between 2008 and 2013 and meeting the following criteria: age >18 years, supratentorial location, post-surgical KPS ≥ 70 %, initially treated with concomitant radiotherapy (RT) and Temozolomide. Within the 84 patients studied, the median PFS was 9 months and the median OS was 18.7 months. The median survival time with functional independence (KPS ≥ 70 %) was 14.5 months. On average, the patients spent 73 % of their lifespan with a KPS ≥ 70 %. Surgical resection and low steroid dosage were statistically associated with increased survival time with KPS ≥ 70 % (p = 0.015 and p = 0.03, respectively). Sixty-two (62) patients received one or several lines of chemotherapy at recurrence. Under treatment with Bevacizumab (42 Bev-based regimens), radiological responses were seen in 35 % and improvement in KPS occurred in 24 % whereas no response and rare improvement of KPS (3 %) were seen with other type of chemotherapy (97 non Bev-based regimens). In GBM patients, median survival with KPS ≥ 70 % largely exceeds PFS. Surgical resection and low steroids dosage at RT-onset appeared as good prognosis factors for survival with functional independence.

Steroid requirements during radiotherapy for malignant gliomas.

Radiotherapy (RT) is the standard treatment for high-grade gliomas. However, toxicity may develop during RT, such as brain edema or worsening of neurological symptoms. Surprisingly, no dedicated study had focused on steroid requirements during RT in adult patients with malignant gliomas. We evaluated prospectively all patients with malignant gliomas treated by RT in a single center from July 2006 to May 2009. Age, sex, initial Karnofsky performance status (KPS), tumor localization and histology, type of surgical resection, clinical target volume, total dose and duration of RT, concomitant treatment with temozolomide, and steroid dosage during RT and at 1 and 3 months after RT were recorded in all patients. Most of the 80 patients (70%) were already taking steroids before RT. Half of them (55%) required initiation or further steroids increase during RT. The median time to steroid increase was 8 days. Only 13% of patients remained free of steroids during RT, and the mean maximal dosage of prednisone was 55 ± 48 mg. At 3 months after RT, 29% of patients were free of steroids, and the mean prednisone dosage was 32 ± 50 mg. Unresected tumors and initial KPS ≤80% were the only variables associated with higher steroid requirements on multivariate analysis. In our series, almost all patients required steroids during RT. Poor initial KPS and biopsy were associated with higher steroid requirements.